Protective Effect of Aerobic High-Intensity Interval Training Against Doxorubicin-Induced Cardiotoxicity in Rats

Authors

  • Khadijeh Ebrahimi1 1- Dept. of Exercise Physiology, Faculty of Physical Education and Sport Sciences, University of Tehran, Aras International Campus, Tehran, Iran. orcid http://orcid.org/0000-0003-2819-2385
  • Siroos Choobineh 2 2- Dept. of Exercise Physiology, Faculty of Physical Education and Sport Sciences, University of Tehran, Tehran, Iran. orcid http://orcid.org/0000-0003-4466-0986
  • Reza Badalzadeh 3 3- Molecular Medicine Research Center and Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz. Iran
  • Rahman Soori 2

DOI:

https://doi.org/10.22100/jkh.v13i3.2040

Keywords:

Doxorubicin, Interval training, Cardiotoxicity, PGC-1α

Abstract

Introduction: Clinical use of Doxorubicin (DOX), a widely useful drug for the treatment of various cancers, is limited by the cardiotoxicity. Despite the growing attention to the protective role of exercise activity, especially moderate endurance exercises against the DOX-induced cardiotoxicity, few studies have focused on aerobic high-interval interval training (AIT) and its mechanisms. Therefore, the purpose of this study was to investigate the protective effect of AIT against the DOX-induced changes in the PGC-1α mRNA levels in the cardiomyocytes of rats.

Methods: 24 male Wistar rats were randomly assigned into four groups (n=6/groups): 1) Control; 2) DOX (20 mg/kg body weight)/; 3) AIT (7 sets of 4 min intervals at 80%–90% VO2max interspersed with 3 min periods of 65%–75% VO2max, for 8 weeks before DOX-injection); and 4) AIT + DOX. The mRNA levels also were determined using RT-PCR. For statistical analysis of data, One-way analysis of variance and Tukey's post hoc test were used (α<0.05).

Results: DOX-treatment significantly decreased the expression of PGC-1α in the DOX group compared to the Control group (P < 0.05). Also, the expression of PGC-1α significantly increased in the AIT group compared to the Control group (P < 0.05). AIT before DOX-induction also significantly increased the expression of PGC-1α in the AIT+DOX group compared to the DOX group (P < 0.05). AIT could inhibit the DOX-induced changes in the PGC-1α mRNA levels in the cardiomyocytes of rats.

Conclusion: AIT could be a good non-prescriptive strategy for preventing of DOX-induced cardiotoxicity.

References

References

Suliman HB, Carraway MS, Ali AS, Reynolds CM, Welty-Wolf KE, Piantadosi CA. The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy. The Journal of clinical investigation 2007;117(12):3730-41. doi:10.1172/JCI32967

Whiteside H, Nagabandi A, Jyothidasan A, Brown K, Thornton J. Acute anthracycline induced cardiotoxicity: A rare and reversible cause of acute systolic heart failure. Journal of the American College of Cardiology 2018;71(11):A2356. doi:10.1016/S0735-1097(18)32897-3

Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 2003;97(11):2869-79. doi:10.1002/cncr.11407

Wallace KB. Doxorubicin‐induced cardiac mitochondrionopathy. Pharmacol Toxicol 2003;93(3):105-15. doi:10.1034/j.1600-0773.2003.930301.x

Zhou S, Starkov A, Froberg MK, Leino RL, Wallace KB. Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin. Cancer Res 2001;61(2):771-7.

Liang H, Ward WF. PGC-1alpha: a key regulator of energy metabolism. Adv Physiol Educ 2006;30(4):145-51. doi:10.1152/advan.00052.2006

Rowe GC, Jiang A, Arany Z. PGC-1 coactivators in cardiac development and disease. Circ Res 2010;107(7):825-38. doi:10.1161/CIRCRESAHA.110.223818

Ventura-Clapier R. Exercise training, energy metabolism, and heart failure. Applied Physiology, Nutrition, and Metabolism 2009;34(3):336-9. doi:10.1139/H09-013

Yang Y, Zhang H, Li X, Yang T, Jiang Q. Effects of PPARα/PGC-1α on the energy metabolism remodeling and apoptosis in the doxorubicin induced mice cardiomyocytes in vitro. Int J Clin Exp Pathol 2015;8(10):12216-24.

Chaube B, Malvi P, Singh SV, Mohammad N, Viollet B, Bhat MK. AMPK maintains energy homeostasis and survival in cancer cells via regulating p38/PGC-1α-mediated mitochondrial biogenesis. Cell death discovery 2015;1:15063. doi:10.1038/cddiscovery.2015.63

Leone TC, Lehman JJ, Finck BN, Schaeffer PJ, Wende AR, Boudina S, et al. PGC-1α deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS biology 2005;3:e101. doi:10.1371/journal.pbio.0030101

Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM, Kelly DP. Peroxisome proliferator–activated receptor γ coactivator-1 promotes cardiac mitochondrial biogenesis. The Journal of clinical investigation 2000;106:847-56. doi:10.1172/JCI10268

Kavazis AN, Smuder AJ, Powers SK. Effects of short-term endurance exercise training on acute doxorubicin-induced FoxO transcription in cardiac and skeletal muscle. Journal of applied physiology 2014;117(3):223-30. doi:10.1152/japplphysiol.00210.2014

Maia TN, Araujo GBRd, Teixeira JAC, Junior A, de Drummond E, Dias KP. Cardiotoxicidade Decorrente do Tratamento com Doxorrubicina e Exercício Físico: Revisão Sistemática. International Journal of Cardiovascular Sciences 2017;30(1):70-80. doi:10.5935/2359-4802.20170004

Marques-Aleixo I, Santos-Alves E, Mariani D, Rizo-Roca D, Padrao AI, Rocha-Rodrigues S, et al. Physical exercise prior and during treatment reduces sub-chronic doxorubicin-induced mitochondrial toxicity and oxidative stress. Mitochondrion 2015;20:22-33. doi:10.1016/j.mito.2014.10.008

Guiraud T, Nigam A, Gremeaux V, Meyer P, Juneau M, Bosquet L. High-intensity interval training in cardiac rehabilitation. Sports medicine 2012;42(7):587-605. doi:10.2165/11631910-000000000-00000

Wang L, Gao K, Wang D. Exercise training has restorative potential on myocardial energy metabolism in rats with chronic heart failure. Iranian Journal of Basic Medical Sciences 2018;21(8):818-23. doi:10.22038/IJBMS.2018.29294.7076

Zuhl M, Kravitz L. Hiit vs. continuous endurance training: battle of the aerobic titans. IDEA Fitness Journal 2012;9:34-40.

Wisløff U, Ellingsen Ø, Kemi OJ. High-intensity interval training to maximize cardiac benefits of exercise training? Exercise and sport sciences reviews 2009;37(3):139-46. doi:10.1097/JES.0b013e3181aa65fc

Jarrett CL, D’Lugos AC, Mahmood TN, Gonzales RJ, Hale TM, Carroll CC, et al. Effect of high intensity exercise preconditioning and training on antioxidant enzymes in cardiomyocytes during doxorubicin treatment. The FASEB Journal 2016;30(1):lb601-lb.

Jiang HK, Wang YH, Sun L, He X, Zhao M, Feng ZH, et al. Aerobic interval training attenuates mitochondrial dysfunction in rats post-myocardial infarction: roles of mitochondrial network dynamics. International journal of molecular sciences 2014;15(4):5304-22. doi:10.3390/ijms15045304

Høydal MA, Wisløff U, Kemi OJ, Ellingsen Ø. Running speed and maximal oxygen uptake in rats and mice: practical implications for exercise training. European Journal of Cardiovascular Prevention & Rehabilitation 2007;14(6):753-60. doi:10.1097/HJR.0b013e3281eacef1

Asadi M, Shanehbandi D, Mohammadpour H, Hashemzadeh S, Sepehri B. Expression level of mir-34a in tumor tissue from patients with esophageal squamous cell carcinoma. Journal of Gastrointestinal Cancer 2018:1-4. doi:10.1007/s12029-018-0060-0

Pfaffl MW. A new mathematical model for relative quantification in real-time RT–PCR. Nucleic acids research 2001;29(9):e45. doi:10.1093/nar/29.9.e45

Mann N, Rosenzweig A. Basic science for clinicians: can exercise teach us how to treat heart disease? Circulation 2012;126(22):2625-35. doi:10.1161/CIRCULATIONAHA.111.060376

Garnier A, Fortin D, Delomenie C, Momken I, Veksler V, Ventura‐Clapier R. Depressed mitochondrial transcription factors and oxidative capacity in rat failing cardiac and skeletal muscles. The Journal of physiology 2003;551(2):491-501. doi:10.1113/jphysiol.2003.045104

Yang Y, Zhang H, Li X, Yang T, Jiang Q. Effects of PPARα/PGC-1α on the myocardial energy metabolism during heart failure in the doxorubicin induced dilated cardiomyopathy in mice. Int J Clin Exp Med 2014;7(9):2435-42.

Ikeda Y, Aihara Ki, Akaike M, Sato T, Ishikawa K, Ise T, et al. Androgen receptor counteracts Doxorubicin-induced cardiotoxicity in male mice. Molecular Endocrinology 2010;24(7):1338-48. doi:10.1210/me.2009-0402

Marechal X, Montaigne D, Marciniak C, Marchetti P, Hassoun SM, Beauvillain JC, et al. Doxorubicin-induced cardiac dysfunction is attenuated by ciclosporin treatment in mice through improvements in mitochondrial bioenergetics. Clinical science 2011;121(9):405-13. doi:10.1042/CS20110069

Ohlig J, Henninger C, Zander S, Merx M, Kelm M, Fritz G. Rac1-mediated cardiac damage causes diastolic dysfunction in a mouse model of subacute doxorubicin-induced cardiotoxicity. Archives of Toxicology 2018;92(1):441-53. doi:10.1007/s00204-017-2017-7

Dolinsky VW, Rogan KJ, Sung MM, Zordoky BN, Haykowsky MJ, Young ME, et al. Both aerobic exercise and resveratrol supplementation attenuate doxorubicin-induced cardiac injury in mice. American Journal of Physiology-Endocrinology and Metabolism 2013;305(2):E243-53. doi:10.1152/ajpendo.00044.2013

Smuder AJ, Kavazis AN, Min K, Powers SK. Doxorubicin-induced markers of myocardial autophagic signaling in sedentary and exercise trained animals. J Appl Physiol 2013;115(2):176-85. doi:10.1152/japplphysiol.00924.2012

Chen JJ, Wu PT, Middlekauff HR, Nguyen KL. Aerobic exercise in anthracycline-induced cardiotoxicity: a systematic review of current evidence and future directions. American Journal of Physiology-Heart and Circulatory Physiology 2017;312(2):H213-22. doi:10.1152/ajpheart.00646.2016

Riehle C, Wende AR, Zhu Y, Oliveira KJ, Pereira RO, Jaishy BP, et al. Insulin receptor substrates (irs) are essential for the bioenergetic and hypertrophic response of the heart to exercise training. Molecular and cellular biology 2014:00426-14. doi:10.1128/MCB.00426-14

Rahimi M, Shekarforoush S, Asgari AR, Khoshbaten A, Rajabi H, Bazgir B, et al. The effect of high intensity interval training on cardioprotection against ischemia-reperfusion injury in wistar rats. EXCLI journal 2015;14:237-46. doi:10.17179/excli2014-587

Karlsen T, Hoff J, Støylen A, Skovholdt MC, Aarhus KG, Helgerud J. Aerobic interval training improves VO2peak in coronary artery disease patients; no additional effect from hyperoxia. Scandinavian Cardiovascular Journal 2008;42(5):303-9. doi:10.1080/14017430802032723

Moholdt TT, Amundsen BH, Rustad LA, Wahba A, Løvø KT, Gullikstad LR, et al. Aerobic interval training versus continuous moderate exercise after coronary artery bypass surgery: a randomized study of cardiovascular effects and quality of life. American heart journal 2009;158:1031-7. doi:10.1016/j.ahj.2009.10.003

Laursen PB. Training for intense exercise performance: high‐intensity or high‐volume training? Scand J Med Sci Sports 2010;20:1-10. doi:10.1111/j.1600-0838.2010.01184.x

Zuhl M, Kravitz L. HIIT vs. Continuous endurance training: Battle of the aerobic titans. IDEA Fitness Journal 2012;9:35-40.

MacInnis MJ, Gibala MJ. Physiological adaptations to interval training and the role of exercise intensity. The Journal of physiology 2017;595:2915-30. doi:10.1113/JP273196

Protective Effect of Aerobic High-Intensity Interval Training Against Doxorubicin-Induced Cardiotoxicity in Rats

Khadijeh Ebrahimi1*, Siroos Choobineh2*, Reza Badalzadeh3, Rahman Soori2

Dept. of Exercise Physiology, Faculty of Physical Education and Sport Sciences, University of Tehran, Aras International Campus, Tehran, Iran.

Dept. of Exercise Physiology, Faculty of Physical Education and Sport Sciences, University of Tehran, Tehran, Iran.

Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz.

Received: 4 October 2018, Accepted: 23 November 2018

;13(3):41-48.

Published

2018-12-16

Issue

Section

Original Article(s)

How to Cite

Protective Effect of Aerobic High-Intensity Interval Training Against Doxorubicin-Induced Cardiotoxicity in Rats. (2018). Knowledge and Health in Basic Medical Sciences, 13(3), 41-49. https://doi.org/10.22100/jkh.v13i3.2040

Most read articles by the same author(s)

1 2 3 4 5 6 7 8 9 10 > >>